Bis(benzoyloxybenzyl)‐DiPPro Nucleoside Diphosphates of Anti‐HIV Active Nucleoside Analogues
Bis(benzoyloxybenzyl)‐DiPPro Nucleoside Diphosphates of Anti‐HIV Active Nucleoside Analogues
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抗 HIV 活性核苷类似物的双（苯甲酰氧基苄基）âDiPPro 核苷二磷酸
DOI：
10.1002/cmdc.201500063
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发表时间：
2015
期刊：
影响因子：
3.4
通讯作者：
C. Meier
中科院分区：
文献类型：
--
作者：
L. Weinschenk;T. Gollnest;D. Schols;J. Balzarini;C. Meier
核苷类似物广泛用作抗病毒和抗癌剂。它们的效率取决于它们代谢成最终活性核苷三磷酸。通常核苷代谢为三磷酸的一步或更多步是低效的。为了克服这一障碍，需要核苷酸的前药。双（酰氧基苄基）核苷二磷酸已被我们报道为有效的核苷二磷酸前药（DiPPro核苷酸）的第一个实例。本文公开了核苷类似物d4 T和AZT的双（苯甲酰氧基苄基）核苷二磷酸的合成和性质。通过使用亚磷酰胺/氧化途径实现合成。在化学水解研究中，大多数化合物形成核苷二磷酸。这在CEM细胞提取物中得到证实，尽管提取物中的前药稳定性低于磷酸盐缓冲液中的前药稳定性。此外，稳定性和形成的核苷二磷酸的量取决于苯甲酰基部分中的取代基。在胸苷激酶缺陷型CEM/TK−细胞中，某些化合物的抗HIV活性高于d4 T或AZT。
Nucleoside analogues are extensively used as antiviral and anticancer agents. Their efficiency is dependent on their metabolism into the ultimately active nucleoside triphosphates. Often one step or even more in the metabolism of the nucleoside to the triphosphate is inefficient. To overcome this hurdle, prodrugs of the nucleotides are needed. Bis(acyloxybenzyl)nucleoside diphosphates have been reported by us as a first example of an efficient nucleosidediphosphateprodrug (DiPPro nucleotides). Here, the synthesis and the properties of bis(benzoyloxybenzyl)nucleoside diphosphates of the nucleoside analogues d4T and AZT are disclosed. The synthesis was achieved by using a phosphoramidite/oxidation route. In chemical hydrolysis studies, most of the compounds formed a nucleoside diphosphate. This was confirmed in CEM cell extracts, although the prodrug stability in extracts was lower than in phosphate buffer. Furthermore, the stability and the amount of nucleoside diphosphate formed were dependent on the substituent in the benzoyl moiety. Some of the compounds were more active against HIV in thymidine kinase‐deficient CEM/TK−cells than were d4T or AZT.